title: Profibrotic effect of miR-33a with Akt activation in hepatic stellate cells.
abstract: MicroRNAs (miRNAs) attract more attention in the pathophysiology of liver fibrosis and miR-33a has been previously demonstrated as involved in the regulation of cholesterol and lipid metabolism. Transforming growth factor-beta1 (TGF-β1) is generally accepted to be the main stimulating factor in the hepatic stellate cells (HSCs) activation, which plays an important role in hepatic fibrosis. However, the involvement and underlying mechanism of miR-33a and its role in TGF-β1-induced hepatic fibrogenesis remains unknown. Here, we investigate the role of miR-33a in the activation of immortalized human HSCs, Lx-2 cells. Our findings have shown that the expression of miR-33a with its host gene sterol regulatory element-binding protein 2 (SREBP2) was more highly expressed in activation of Lx-2 cells than in quiescent cells. The expression of miR-33a on TGF-β1-induced HSCs activation may be modulated via the activation of PI3K/Akt pathway. In addition, miR-33a significantly correlated with TGF-β1-induced expression of α1 (I) collagen (Col1A1) and α-SMA in HSCs. Bioinformatics analyses predict that peroxisome proliferator activated receptor-alpha (PPAR-α) is the potential target of miR-33a. We further found that anti-miR-33a significantly increases target gene PPAR-α mRNA and protein level, suggesting that miR-33a involved in HSCs function might be modulated by targeting PPAR-α. Finally, our results indicate that the expression of miR-33a increased with the progression of liver fibrosis. These results suggested that anti-miR-33a inhibit activation and extracellular matrix production, at least in part, via the activation of PI3K/Akt pathway and PPAR-α and anti sense of miR-33a may be a novel potential therapeutic approach for treating hepatic fibrosis in the future.
authors.affiliation: College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China. Electronic address: zhuojianli@163.com.
authors.forename: Zhuo-Jian
authors.initials: ZJ
authors.lastname: Li
authors.forename: Pai-Huai
authors.initials: PH
authors.lastname: Ou-Yang
authors.forename: Xing-Peng
authors.initials: XP
authors.lastname: Han
mesh_terms: D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D006801:Humans; D008103:Liver Cirrhosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D047493:PPAR alpha / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; D047493:PPAR alpha; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D053773:Transforming Growth Factor beta1; D051057:Proto-Oncogene Proteins c-akt
keywords: Hepatic stellate cells; PI3K/Akt; PPAR-α; TGF-β1; miR-33a; α-smooth muscle actin